COXIBs for dysmenorrhoea
Bandolier 120 looked at a systematic review [1] of NSAIDs for dysmenorrhoea, and the question arose about effectiveness of newer coxibs. A search found four randomised trials and the results appear below, but these coxib trials differed from the NSAID trials in the outcomes used, so a brief digression into trial designs is needed before we get to the results.
Pain with dysmenorrhoea usually lasts for about three days, though with considerable individual variation. Trials of analgesics can have various forms. The simplest might be to give the same analgesic for the whole of the painful cycle, and ask a global question concerning efficacy at the end. Women might then be crossed over to a different treatment at the next cycle. This was the design used for NSAID comparisons with placebo, with the outcome of at least moderate pain relief over the cycle.
A variation would be to use the same basic structure, but make more detailed evaluations of pain or pain relief over a limited time during the first day. This was the approach used in the coxib trials.
Coxib trials
Bandolier searched PubMed for randomised trials comparing any coxib (celecoxib, etoricoxib, lumaricoxib, rofecoxib, valdecoxib) with placebo or analgesic in women with painful dysmenorrhoea. Four published trials [2-5] were found (Table 1). All investigated the analgesic efficacy of a first dose in women with moderate or severe menstrual pain. All included both placebo and naproxen sodium 550 mg. Three were double blind, and one [3] was an open study that also had a global outcome over the cycle, but compared with once-daily naproxen sodium 550 mg, rather than the usual dose of twice daily naproxen.
Table 1: Individual randomised trials comparing a coxib with placebo and/or NSAID in dysmenorrhoea
| Reference | Design | Treatments (women) |
Outcomes | Results |
| Morrison et al, 1999 | Randomised, double blind, comparison of rofecoxib 25 and 50 mg, naproxen sodium 550 mg and placebo. First dose efficacy, crossover between menses in 127 women | Placebo (118) Rofecoxib 25 mg (115) Rofecoxib 50 mg (118) Naproxen sodium 550 mg (122) First dose, then every 12 hours as needed (once daily rofecoxib 25 mg, twice daily naproxen) |
Pain relief and intensity over first 8 hours Peak relief Additional medication in first 12 hours Additional analgesia in 12-72 hours |
All active better than placebo, except additional
analgesics taken 12-72 hours No difference between analgesics No adverse event difference, and no serious adverse events |
| Sahin et al, 2003 | Randomised, open comparison of rofecoxib 25 and 50 mg, naproxen sodium 550 mg and placebo. First dose efficacy, crossover between menses in 55 women | Placebo (55) Rofecoxib 25 mg (55) Rofecoxib 50 mg (55) Naproxen sodium 550 mg (55) First dose, then once daily as needed |
Pain intensity over first 24 hours Overall analgesic efficacy score over the cycle Pill count |
All active better than placebo for pain
intensity "Perfect" global efficacy in 90% with rofecoxib (both doses), and 33% with naproxen Total pills taken lower for rofecoxib than placebo 64% gastrointestinal adverse events for naproxen |
| Daniels et al, 2002 | Randomised, double blind, comparison of valdecoxib 20 and 40 mg, naproxen sodium 550 mg and placebo. First dose efficacy, crossover between menses in 30 women | Placebo (29) Valdecoxib 20 mg (30) Valdecoxib 40 mg (30) Naproxen sodium 550 mg (29) First dose, then twice daily as needed |
Pain relief and intensity over first 8 and 12
hours Global assessment at 12 hours Additional medication in first 12 hours |
All active better than placebo, except additional
analgesics taken over 12 hours, where both valdecoxib doses but not naproxen
had fewer than placebo No difference between analgesics No adverse event difference |
| Malmstrom et al, 2003 | Randomised, double blind, comparison of etoricoxib 120 mg, naproxen sodium 550 mg and placebo. First dose efficacy, crossover between menses in 73 women | Placebo (73) Etoricoxib 120 mg (73) Naproxen sodium 550 mg (73) First dose only |
Pain relief and intensity over 24 hours Analgesia onset Peak relief Additional medication in first 12 hours |
Both active treatments same, and better than placebo for relief over first 8 hours, and other outcomes. No adverse event difference, and no serious adverse events |
Results
Over the first 8-24 hours, all analgesics were better than placebo, but there was no difference between coxibs and naproxen sodium 550 mg for any analgesic measurement, or use of additional analgesic therapy. Only one trial [4] provided a patient outcome of good or excellent response over 12 hours, which gave numbers needed to treat compared with placebo of about 3 for naproxen sodium 550 mg and valdecoxib 40 mg, and 4 for valdecoxib 20 mg. Over a cycle in the open trial [3] both 25 mg and 50 mg daily rofecoxib was better than naproxen sodium 550 mg.
Adverse events did not differ between groups, though a very high rate of gastrointestinal adverse events (64%) was reported for naproxen sodium in the open trial [3]. Discontinuations were infrequent.
Comment
There were 285 women in these four studies, almost all of whom had both placebo and naproxen sodium 550 mg. This is more than the 180 or so women in trials of naproxen and placebo in the systematic review of NSAIDs [1], so these four trials constitute an important addition to knowledge, even if one of them was open. They all come up with the same answer, namely that coxibs at standard doses are equivalent to naproxen sodium 550 mg over eight to 12 hours after the first dose at the onset of menstrual pain.
These outcomes are, of course, important for regulatory authorities, but are less helpful for every day consideration, though once-daily dosing for some coxibs is a theoretical benefit. What was missing was more woman-centred outcomes, and, also, information on adverse events over a cycle, in sufficient numbers of women to spot a difference. Were these outcomes actually captured in the trials, but not reported because they are of little interest to regulatory agencies? It would be fascinating to know. So while we move on a bit, we have still to make the great leap forward.
References:
- J Marjoribanks J et al. Nonsteroidal anti-inflammatory drugs for primary dysmenorrhoea (Cochrane Review). In: the Cochrane Library, Issue 4, 2003.
- BW Morrison et al. Rofecoxib, a specific cyclooxygenase-2 inhibitor, in primary dysmenorrhoea: a randomized controlled trial. Obstetrics & Gynecology 1999 94:504-508.
- I Sahin et al. Dysmenorrhea treatment with a single daily dose of rofecoxib. International Journal of Gynecology & Obstetrics 2003 83: 285-291.
- SE Daniels et al. Valdecoxib, a cyxlooxygenase-2-specific inhibitor, is effective in treating primary dysmenorrhoea. Obstetrics & Gynecology 2002 100:350-358. 5 K Malmstrom et al. Analgesic efficacy of etoricoxib in primary dysmenorrhea: results of a randomized, controlled trial. Gynecologic and Obstetric Investigation 2003 56: 65-69.